Wednesday, June 22, 2016

As a second generation Floridian growing up in the 1950s, one who collected mosquito bites the way most kids collected marbles, I'm well of aware of the itchy misery they can inflict.

But we've new evidence - published yesterday in the journal Immunity - suggesting that the mozzie's itch inducing saliva may also set up a host response that helps spread arboviruses like Dengue, CHKV, and Zika throughout the body.

Aedes aegypti mosquitoes are responsible for transmitting many medically important viruses such as those that cause Zika and dengue. The inoculation of viruses into mosquito bite sites is an important and common stage of all mosquito-borne virus infections.

We show, using Semliki Forest virus and Bunyamwera virus, that these viruses use this inflammatory niche to aid their replication and dissemination in vivo. Mosquito bites were characterized by an edema that retained virus at the inoculation site and an inflammatory influx of neutrophils that coordinated a localized innate immune program that inadvertently facilitated virus infection by encouraging the entry and infection of virus-permissive myeloid cells. Neutrophil depletion and therapeutic blockade of inflammasome activity suppressed inflammation and abrogated the ability of the bite to promote infection.

This study identifies facets of mosquito bite inflammation that are important determinants of the subsequent systemic course and clinical outcome of virus infection.

The full study is an interesting, albeit technical, read. For those looking for a plain language summary, the University of Leeds has published a press release:

Mosquito bite sites are not just itchy, irritating nuisances - they also make viral infections spread by the insects far worse, new research has found.

The study, led by the University of Leeds, found that inflammation where the insect has bitten not only helps a virus such as Zika or dengue establish an infection in the body more quickly, but that it also helps it to spread around the body, increasing the likelihood of severe illness.

"Mosquito bites are not just annoying - they are key for how these viruses spread around your body and cause disease," said Dr Clive McKimmie, a research fellow at the School of Medicine and senior author of the study.

"We now want to look at whether medications such as anti-inflammatory creams can stop the virus establishing an infection if used quickly enough after the bite inflammation appears."

In the new research, published in the journal Immunity, the investigators used mouse models to study the bites of the Aedes aegypti mosquito, the species that spreads infections such as Zika, dengue and Chikungunya.

When a mosquito bites, it injects saliva into the skin. The saliva triggers an immune response in which white blood cells called neutrophils and myeloid cells rush to the site.

But instead of helping, some of these cells get infected and inadvertently replicate the virus, the researchers found.

The team injected viruses into the skin of the mice with or without the presence of a mosquito bite at the injection site and compared the reaction.

In the absence of mosquito bites and their accompanying inflammation, the viruses failed to replicate well, whereas the presence of a bite resulted in a high virus level in the skin.

"This was a big surprise we didn't expect," said Dr McKimmie, whose team worked alongside colleagues at the University of Glasgow. "These viruses are not known for infecting immune cells.

"And sure enough, when we stopped these immune cells coming in, the bite did not enhance the infection anymore."

Despite the enormous disease burden of mosquito-borne viral infections - they are responsible for hundreds of millions of cases across the world - there are few specific therapies or vaccines.

"This research could be the first step in repurposing commonly available anti-inflammatory drugs to treat bite inflammation before any symptoms set in", said Dr McKimmie, whose study was funded by the Medical Research Council.

"We think creams might act as an effective way to stop these viruses before they can cause disease."

He added that if it is proven to be effective, this approach could work against a multitude of other viruses.

"Nobody expected Zika, and before that nobody expected Chikungunya," he said.

"There are estimated to be hundreds of other mosquito-borne viruses out there and it's hard to predict what's going to start the next outbreak."